Preclinical study outlines cardiovascular side effects of breast cancer drug

July 13, 2016, University of Pennsylvania School of Medicine
A visualization of the coronary vasculature patterning of an adult mouse heart. Credit: Haig Aghajanian, PhD, Perelman School of Medicine at the University of Pennsylvania

A receptor protein that is the target of the breast cancer drug trastuzumab (Herceptin) is needed for proper heart blood-vessel development, reported researchers from the Perelman School of Medicine at the University of Pennsylvania. They published their findings this month in Nature Communications. These discoveries have implications for better understanding the cardiovascular side effects of trastuzumab commonly used for cancer and provide an example of integration at the molecular level of pathways involved in tissue growth and blood-vessel patterning.

First author Haig Aghajanian, PhD, a postdoctoral fellow in the lab of senior author Jon Epstein, MD, a professor of Cell and Developmental Biology and executive vice dean and chief scientific officer for Penn Medicine, showed that ErbB2, a growth factor receptor, is unexpectedly expressed by . Here it partners with neuropilin 1 to form a receptor for the vascular guidance molecule semaphorin 3d. Guidance molecules work by instructing the direction in which cells migrate, such as when new blood vessels are forming.

"ErbB2 is a well known target in cancer therapy, but not in vascular biology," Aghajanian said. "Our work identifies a new role for this important protein in blood vessel development and gives us a possible explanation for some of the cardiovascular associated with anti-ErbB2 therapies."

They found that the loss of semaphorin 3d leads to improper connections of the coronary veins forming within the developing heart. They found a similar effect when ErbB2 was lost from developing heart-vessel-lining cells, providing a genetic link between these pathways.

The team was surprised when ErbB2 came up in their search for molecular partners for semaphorin 3d because semaphorin guidance molecules are not typically known to work through ErbB receptors.

"We questioned ErbB2's role at first," Epstein said. (ErbB2 had not previously been shown to even be in blood vessels.) "But now these findings give us a possible explanation for why there can be serious cardiovascular side effects, including heart failure, in patients receiving anti-ErbB2 therapies such as Herceptin."

Aghajanian and Epstein are using this knowledge to refine the hypothesis that targeting ErbB2 may also affect heart blood vessels leading to unwanted side effects. A better understanding of why the deleterious side effects are produced may lead to better ways to monitor and detect these unwanted effects before they cause symptoms.

"This work adds to an array of signals that affect how vessels grow and offers more targets to develop that promote or block the growth of ," Epstein said. These new targets could have implications for stopping the growth of certain tumors, abating ischemia, and alleviating diabetic retinitis.

Explore further: Team discovers new mechanism of acquired resistance to breast cancer drugs

Related Stories

Team discovers new mechanism of acquired resistance to breast cancer drugs

February 2, 2015
In the search for new approaches to treat ERBB2 (also known as HER2) positive breast cancers that have become drug-resistant, Dartmouth's Norris Cotton Cancer Center investigator Manabu Kurokawa, PhD, led a team in discovery ...

Researchers identify mechanism that makes breast cancer invasive

March 29, 2012
A new study has identified a key mechanism that causes breast cancer to spread. The research, published by Cell Press on March 30th in the journal Molecular Cell, enhances our knowledge about the signals that drive cancer ...

Going to 'Wars' against cancer and heart disease

July 8, 2016
In a study conducted by Duke-NUS Medical School (Duke-NUS) and the National Heart Centre Singapore (NHCS), researchers discovered a new gene that controls blood vessel formation. This work presents a possible new drug target ...

Overcoming barriers in the quest to starve tumors of blood supply

July 13, 2016
One of the most exciting strategies researchers are pursuing for fighting cancer is to cut off the blood supply of cancerous cells. However, many initially-promising therapies have failed in part because tumor cells counteract ...

New treatment target identified for aggressive breast cancer

October 14, 2014
One of the first-known oncogenes has a protein partner that helps breast cancer proliferate and when it's blocked, so is the cancer, scientists report.

Newly engineered CAR T cells can better discriminate between cancer and normal cells

September 1, 2015
A new development in engineering chimeric antigen receptor (CAR) T cells, called affinity tuning, can make the CAR T cells spare normal cells and better recognize and attack cancer cells, which may help lower the toxicity ...

Recommended for you

Healthy diets linked to better outcomes in colorectal cancer

October 20, 2018
Colorectal cancer patients who followed healthy diets had a lower risk of death from colorectal cancer and all causes, even those who improved their diets after being diagnosed, according to a new American Cancer Society ...

Why some cancers affect only young women

October 19, 2018
Among several forms of pancreatic cancer, one of them specifically affects women, often young. How is this possible, even though the pancreas is an organ with little exposure to sex hormones? This pancreatic cancer, known ...

Scientists to improve cancer treatment effectiveness

October 19, 2018
Together with researchers from the University of Nantes and the University of Reims Champagne-Ardenne in France, experts from the National Research Nuclear University MEPhI have recently developed a quantum dot-based microarray ...

Mutant cells colonize our tissues over our lifetime

October 18, 2018
By the time we reach middle age, more than half of the oesophagus in healthy people has been taken over by cells carrying mutations in cancer genes, scientists have uncovered. By studying normal oesophagus tissue, scientists ...

Study involving hundreds of patient samples may reveal new treatment options of leukemia

October 17, 2018
After more than five years and 672 patient samples, an OHSU research team has published the largest cancer dataset of its kind for a form of leukemia. The study, "Functional Genomic Landscape of Acute Myeloid Leukemia", published ...

A 150-year-old drug might improve radiation therapy for cancer

October 17, 2018
A drug first identified 150 years ago and used as a smooth-muscle relaxant might make tumors more sensitive to radiation therapy, according to a recent study led by researchers at The Ohio State University Comprehensive Cancer ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.